PREDICT-HD is an international 30-site observational study of persons at-risk for Huntington's disease (HD). PREDICT-HD capitalizes on two unique aspects of HD among neurodegenerative disorders the ability to know in advance who will develop the disease and the knowledge that all affected individuals have the same etiology (a CAG expansion in the huntingtin gene). PREDICT-HD has become part of a world-wide effort and offers an unprecedented opportunity to examine the pathophysiology and neurobiology of early HD. We seek renewal of this project to maximize the impact of this resource and test new and refined hypotheses to advance clinical trials in HD. The ultimate goal of PREDICT-HD is to define the neurobiology of HD sufficiently to allow clinical trials of potential disease-modifying therapies before at-risk individuals have diagnosable symptoms of the disease. By identifying disease state markers that are useful during this early period, PREDICT-HD will make it possible to test putative neuroprotective therapies that could delay or prevent the manifestations of disease. PREDICT-HD has successfully recruited over 1000 healthy participants who had previously undergone genetic testing for the HD expansion. Annual measures of plasma, brain imaging, cognitive performance, psychiatric symptoms, and functional capacity are obtained in concert with other demographic, clinical and genetic information. We have already identified markers of disease that are present 15 years prior to traditional motor diagnosis. The requested 5-year longitudinal continuation of PREDICT-HD will result in six products: (1) Characterization of the early longitudinal course of functional, cognitive, motor, and psychiatric change in the period encompassing 10-20 years before to 0-3 years after the traditional point of clinical diagnosis. (2) Identification of candidate biological and neuroimaging markers that have potential as useful biomarkers and possibly as surrogate endpoints in clinical trials. Developed appropriately, markers identified in PREDICT-HD could be used to reduce dramatically the number of subjects needed in future clinical trials, and/or to stratify subjects for selection in studies. (3) Refinement and standardization of the measurement of neurological and functional impairment in the earliest stages of HD development, including the point of traditional clinical diagnosis. (4) Provision of a cohort from which sub samples may volunteer for early (phase I and II) trials of candidate therapies as well as phase III efficacy trials. (5) Examination of available compounds for safety and tolerability and of their impact on newly developed disease state markers in this presymptomatic cohort. (6) Innovations in infrastructure and worldwide collaboration to serve as a model and catalyst for clinical trials in other neurodegenerative diseases.